In tumor cell, cellular uptake of sugar and amino acid is enhanced for the rapid growth and the increased intracellular metabolism. The uptake is achieved by the increased functional activity and expression of transporters which play roles in cellular uptake of the nutrients. Amino acid transporters which supply essential amino acids to tumor cell are considered to be the rate-limiting steps of tumor cell growth, and therefore, the tumor growth can be controlled by suppression of the function.
Amino acid transporters are classically-known as amino acid transport systems, and many transport systems have been identified based on diversity of amino acid molecules. In tumor cell, many of essential amino acids belonging to neutral amino acids are supplied to cell via a transport system called system L. The system L is a transport system which selectively transports neutral amino acids having a bulky side chain such as branched amino acids, aromatic amino acids and the like, and it has been known as amino acid uptake inhibitor BCH (2-aminobicyclo[2.2.1]heptane-2-carboxylic acid)-sensitive transport system in the 1960's (Non-Patent Document 1).
By subsequent study, system L has been identified as twelve-transmembrane protein LAT-1 of SLC7 family (Non-Patent Document 2). In addition, it has been demonstrated that single-transmembrane protein 4F2hc (4F2 heavy chain; 4F2 heavy chain; CD98; SLC3A2) is essential to maintain the LAT-1 activity. The complex of LAT-1 and 4F2hc, which is formed via a disulfide bond, Na+-independently transports neutral amino acids having a bulky side chain such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, histidine and the like, and is suppressed by the above-mentioned system L-specific inhibitor BCH, and functions as a transporter showing characteristics of classical system L (Non-Patent Documents 2 and 3).
LAT-1 expression in normal tissue is limited to in brain, placenta, bone marrow, testis and the like, and the expression level is high in fetus liver, but low in adult liver. Therefore, this fact suggests that LAT-1 is carcinoembryonic antigen (Non-Patent Documents 2 and 3). The partial LAT-1 sequence has been already reported as a cancer-related sequence TA1 (Tumor-associated gene 1) wherein the function is unidentified (Non-Patent Document 4). It has been demonstrated that the LAT-1 expression is increased together with 4F2hc expression and shows characteristic distribution in primary lesion and metastasis of many human malignant tumor tissue such as colorectal cancer, stomach cancer, breast cancer, pancreatic cancer, renal cancer, prostate cancer, larynx cancer, esophageal cancer, lung cancer, brain tumor, head and neck carcinoma, genital cancer, soft tissue sarcoma and the like (Non-Patent Documents 5 to 10). In addition, it has been demonstrated that the LAT-1 expression correlates with patient prognosis in malignant tumor, and LAT-1 high expression leads to poor prognosis (Non-Patent Documents 6 to 9). LAT-1-selective substrate, 123I-IMT (3-123I-iodo-a-methyl-L-tyrosine) is used for SPECT (Single photon emission computed tomography) diagnosis of malignant tumor, and LAT-1-selective substrate, 18F-FAMT (L-[3-18F]-a-methyltyrosine) is used for PET (positron emission tomography) diagnosis of malignant tumor (Non-Patent Documents 11 and 12). It has been demonstrated by PET using 18F-FAMT that 18F-FAMT accumulation correlates with LAT-1 protein expression (Non-Patent Documents 12 and 13). FAMT is accumulated selectively in malignant tumor, whereas poorly in benign lesion and normal tissue, and therefore, it has been conclusively demonstrated that LAT-1 is expressed selectively in malignant tumor (Non-Patent Document 12).
It has been demonstrated that the above-mentioned BCH shows tumor cell growth inhibitory effect in vitro and tumor enlargement inhibitory effect and survival advantage of cancer-bearing mice in vivo (Non-Patent Documents 9 and 14). In addition, tumor cell growth inhibitory effect in vitro and tumor enlargement inhibitory effect in vivo of amino acid derivative, LAT-1 competitive inhibitor KYT-0353 have been disclosed (Non-Patent Document 15 and Patent Document 1). Thus, it has been already demonstrated that anti-tumor effect is achieved by inhibition of LAT-1.
As LAT-1 inhibitors, the above-mentioned system L-specific inhibitor BCH has been synthesized in the 1960's. However, the inhibitor has low affinity and no LAT-1 selectivity. Recently, as an inhibitor having LAT-1 selective and high affinity, the above-mentioned KYT-0353 has been synthesized (Non-Patent Document 15 and Patent Document 1). However, both BCH and KYT-0353 are competitive inhibitors, and the actions are reduced in vivo having a high concentration of amino acid. Therefore, it is expected that high doses thereof are requested to achieve sufficient effects.
As compounds having a structure similar to that of the phenoxyalkylamine compounds of the present invention, for example, alkylamine compounds having a phenoxy group have been reported in Patent Document 2.
whereinX and Y are each independently C1-4 alkyl, C1-4 alkoxy, halogen, CF3, OCF3 or the like,m and p are each independently 0 or 2,Z is H or F,V is O, S(O)n or NR3,W is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-4 cycloalkyl, a 4- to 8-membered saturated heterocyclic group or the like (each is optionally substituted by C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halogen and the like), or phenyl or a 5- or 6-membered aromatic heterocyclic group (each is optionally substituted by halogen, C1-4 alkyl, C1-4 alkoxy, OH, CN and the like),R1 and R2 are each independently H, C1-4 alkyl or C3-4 cycloalkyl, or R1 and R2 in combination form a 4- to 8-membered saturated nitrogen-containing heterocyclic group, andR3 is H or C1-4 alkyl.
In addition, alkylamine compounds having a phenoxy group have also been reported in Patent Document 3.
whereinR1 and R2 are each independently H, halogen, C1-4 alkyl, C1-4 alkoxy, halo-substituted C1-4 alkyl, halo-substituted C1-4 alkoxy or OH, andR3 is C1-4 alkyl.